Prediction of intrahepatic covalently closed circular DNA levels in patients with resolved hepatitis B virus infection: Impact of serum antibody to hepatitis B core antigen titers

Abstract

Aim

The correlation between intrahepatic covalently closed circular DNA (cccDNA) levels and serum hepatitis B virus (HBV) markers in patients with resolved HBV infection (hepatitis B surface antigen [HBsAg]-negative and antibody to hepatitis B core antigen [anti-HBc]-positive) is unclear. We therefore examined the utility of anti-HBc titers as a surrogate marker of intrahepatic cccDNA levels in patients with resolved HBV infections.

Methods

Among 1005 patients who underwent hepatectomy between 2010 and 2018, a retrospective review was performed in 114 patients (76 with resolved HBV infection and 38 HBsAg-positive) with frozen specimens of the background liver. Clinical, biochemical, and virological data, including intrahepatic cccDNA levels, were retrospectively evaluated. Intrahepatic cccDNA levels were measured using droplet digital polymerase chain reaction.

Results

Intrahepatic cccDNA levels positively correlated with serum HBsAg levels (r = 0.609, p < 0.001) and anti-HBc titers (r = 0.542, p < 0.001). An intrahepatic cccDNA level of 22.2 copies/μg was the optimal cut-off for HBsAg positivity, with a sensitivity of 86.8% and specificity of 89.5%. Of the 76 cases with resolved HBV infection, 8 had high levels of intrahepatic cccDNA (≥22.2 copies/μg). Multivariate analyses showed that anti-HBc ≥ 11.0 sample/cut-off (S/CO) was an independent risk factor for high intrahepatic cccDNA levels (odds ratio, 12.6; 95% confidence interval, 2.4–66.156; P = 0.003).

Conclusions

Anti-HBc titers were positively correlated with intrahepatic cccDNA levels. Even in patients with resolved HBV infection, anti-HBc ≥ 11.0 S/CO was considered to indicate high intrahepatic cccDNA levels, comparable to those in HBsAg-positive cases. In this group, careful monitoring is required during immunosuppressive therapy to prevent HBV reactivation.